The sense of touch is unique in perceiving stimuli both physical (temperature, mechanical) and chemical (compounds that cause pain, itch, et cetera) in nature. In each modality, touch neurons distinguish noxious (painful) from innocuous stimuli, and the sensitization of touch neurons in response to injury and inflammation is the basis for many clinically-relevant chronic pain states. The molecules that mediate detection of touch stimuli have been a long-standing mystery. Recently, we and others have identified and characterized molecules responsible for sensing environmental temperature. These proteins are ion channels activated by distinct changes in thermal energy (in the noxious to innocuous range), thus functioning as the molecular thermometers of our body. We have found these same ion channels also act as chemosensors, and at least one of them is a polymodal sensor of physical and chemical damage. We wish to understand the activation process of thermoTRPs. Most fundamentally, how do these channels actually sense temperature at the molecular level? We will use a high- throughput random mutagenesis approach to address mechanism of thermoTRP activation. Our long-term goal is to synthesize a detailed molecular understanding of somatosensory neuron function. These studies aim to expand the fundamental understanding of basic sensory biology and are also expected to contribute to novel insights to treating pain. PUBLIC HEALTH RELEVANCE The studies described in this grant will address how ion channels involved in sensing pain and temperature are regulated. Information from these studies could potentially help in designing analgesic drugs.